Fig. 5. (A) Periodic box with solvated M^pro-C33 complex. (B) Top: plot of total energy of the system during the 200 ns simulation in Desmond³² (〈E〉 = −78 018 ± 32 kcal mol⁻¹), middle: potential energy (〈E_p〉 = −97 311 ± 28 kcal mol⁻¹), bottom: temperature (〈T〉 = 299.4 ± 0.2 K). (C) Analysis of enzyme-inhibitor interactions. Top: contribution of individual active site residues to inhibitor binding (HB – green, ionic interactions – magenta, hydrophobic – purple, water bridges – blue); middle: number of favourable contacts between the M^pro and C33, bottom: time-evolution of the interactions between inhibitor and individual active site residues. (D) 2D representation of the most populated attractive interactions between C33 and individual active site residues of SARS-CoV-2 M^pro occurring at least in 1/3 of the 500 analysed frames. (E) Evolution of properties of the bound inhibitor during the simulations. Top to bottom: root mean square deviation from the initial structure (RMSD), radius of gyration (rGyr), number of intramolecular hydrogen bonds (intraHB), molecular surface area (MolSA), solvent-accessible surface area (SASA), and polar surface area (PSA).